The growth hormone (GH) / insulin-like growth factor-l (IGF-I) axis is a powerful mediator of skeletal muscle[unreadable] growth. IGF-I is also known to be an important mediator of the adaptation of skeletal muscle to increased[unreadable] loading. The "proinflammatory" cytokine interleukin -6 (IL-6) is primarily involved with the immune response[unreadable] to infection. In many settings the functions of IL-6 are known to induse a catabolic state in skeletal muscle.[unreadable] There is evidence that some components of the intracellular signaling pathways that are activated by IGF-I[unreadable] and/or GH are shared with signaling stimulated by IL-6. These common elements include components of the[unreadable] JAK/STAT/SOCS signaling and negative feed back system. Paradoxically, common forms of exercise have[unreadable] been shown to increase plasma IL-6 and to depress circulating IGF-I. We present preliminary data which[unreadable] demonstrates that relatively low doses of IL-6, comparable to those seen in humans following exercise, can[unreadable] initiate a catabolic response in skeletal muscle. We hypothesize that elevated muscle levels of IL-6 interact[unreadable] with and negatively impact the anabolic effects of GH and IGF-I in skeletal muscle in vivo. We speculate that[unreadable] one of the mechanisms by which IL-6 mediates this impact is via the activation of SOCS feedback resulting[unreadable] in alterations in IGF-I and GH mediated intracellular signals. We propose experiments designed to:1)[unreadable] characterize IL-6 signaling in muscle; 2) characterize GH signaling in muscle; 3) identify the mechanisms by[unreadable] which IL-6 interacts with and alters GH and IGF-I signaling; 4) identify the mechanisms by which IL-6[unreadable] interacts with and alters the adaptation of skeletal muscle to increased loading ; 5) identify the mechanisms[unreadable] by which IL-6 impacts the growth and development of skeletal muscle. Our approach is based on the in vivo[unreadable] local muscle infusion model developed by our team. In contrast to the methods currently found in the[unreadable] literature, this approach allows for the direct (i.e., non-systemic) delivery of growth factors and cytokines into[unreadable] a single targeted skeletal muscle. In our previous funding period we demonstrated that this approach can be[unreadable] used to manipulate intracellular signaling pathways and allow for the identification of mechanisms that[unreadable] mediate the response to growth factors. The studies outlined in this proposal will add to our understanding[unreadable] of the role of exercise induced elevations in IL-6 with regard to its impacts on muscle growth and adaptation.